MBD5-associated neurodevelopmental disorder

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

MBD5-associated neurodevelopmental disorder (MAND) is a condition that affects neurological and physical development.

Children with MAND have mild to severe intellectual disability and developmental delay. They often have poor coordination and do not walk until age 2 or 3. Their walking style (gait) is often unbalanced and wide-based. Language skills, both the production of speech and the ability to understand speech, are very limited in affected individuals. By age 2, most children with MAND develop recurring seizures (epilepsy). Most affected children have feeding problems due to weak muscle tone (hypotonia). Constipation also frequently occurs.

Sleep problems are common in MAND and include night terrors, waking frequently during the night, and waking early in the morning. As a result, many affected individuals are extremely tired during the day due to lack of sleep and poor-quality sleep. Most people with MAND have features similar to autism spectrum disorder, a developmental condition that affects communication and social interaction. They have a short attention span; perform repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; and grind their teeth.

People with MAND tend to have subtle facial features, including a broad forehead, thick and highly arched eyebrows, abnormalities of the outer ear, a short nose, a wide or depressed nasal bridge, downturned corners of the mouth, an upper lip that points outward (called a tented lip), and a full lower lip. Some affected individuals have mild skeletal abnormalities including small hands and feet, short fingers (brachydactyly), curved pinky fingers (fifth-finger clinodactyly), or a wide gap between the first and second toes (known as a sandal gap). Rarely, individuals with MAND have heart abnormalities.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

MAND is most often caused by a loss (deletion) or gain (duplication) of genetic material in a particular region of chromosome 2. These changes are also known either as 2q23.1 microdeletions or 2q23.1 microduplications. The missing or extra region varies in length from a few thousand to a few million DNA building blocks (base pairs) but always includes the MBD5 gene. Less frequently, MAND is caused by mutations that affect only the MBD5 gene. Because mutations in the MBD5 gene and changes on chromosome 2 that involve this gene both cause MAND, researchers believe that MBD5 gene changes underlie most of the signs and symptoms of the condition. Neurological features of the condition generally do not differ based on the genetic cause, although they can vary between individuals.

The MBD5 gene provides instructions for a protein that likely regulates the activity (expression) of genes, controlling the production of proteins that are involved in neurological functions such as learning, memory, and behavior. The MBD5 protein also seems to play a role in the growth and division (proliferation) and maturation (differentiation) of various types of cells.

All of the genetic changes associated with MAND lead to an abnormal amount of MBD5 protein. MBD5 gene mutations and deletions prevent one copy of the MBD5 gene in each cell from producing any functional protein, which reduces the total amount of this protein in cells. A duplication leads to an increased amount of MBD5 protein. It is likely that any changes in MBD5 protein levels impair its regulation of gene expression, leading to the uncontrolled production of certain proteins. Proteins that play a role in neurological functions are particularly affected, which helps explain why MAND impacts brain development and behavior. An increase or decrease in MBD5 protein disrupts gene expression that is normally well-controlled by this protein, which is likely why duplications and deletions involving the MBD5 gene lead to the same signs and symptoms. The cause of the skeletal abnormalities and other non-neurological features of MAND is unclear. It is also unknown whether the loss or gain of other genes in chromosome 2 deletions or duplications contributes to the variable features of MAND.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

MAND is considered an autosomal dominant condition because one copy of the altered chromosome 2 or MBD5 gene in each cell is sufficient to cause the disorder. Most cases of MAND are not inherited but occur as random events during the formation of reproductive cells (eggs or sperm) in a parent of an affected individual. These cases occur in people with no history of the disorder in their family. In a small percentage of cases, people with MAND inherit the altered chromosome or gene from a parent with the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

MAND is thought to be a rare disorder, although its prevalence is unknown. More than 100 affected individuals have been described in the scientific literature.

Which doctor should you see?

The suggested department for discussing MBD5-associated neurodevelopmental disorder is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for MBD5-associated neurodevelopmental disorder. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.